Physiology of excitable cells
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2015
The motor nerve action potential depolarizes the nerve terminal and releases acetylcholine from the synaptic vesicles into the junctional cleft. Acetylcholine excites the postjunctional nicotinic receptors, depolarizes the end plate and generates a propagated action potential in the surrounding muscle membrane (Figure 1.27). Muscle shortening then follows by the process of excitation–contraction coupling. Acetylcholine is soon metabolized by acetylcholinesterase, and the end plate returns to the resting state. Neuromuscular transmission is an amplification process whereby a nerve action potential produces a much larger muscle action potential. Acetylcholine therefore has a central role in the process of neuromuscular transmission (Figure 1.28).
The Problems
John Greene, Ian Bone in Understanding Neurology a problem-orientated approach, 2007
The motor unit comprises the anterior horn cell or motor neurone, its axon, and the muscle fibres innervated by that axon (117). The number of muscle fibres supplied by a single motor neurone is variable and is dependent on the function of the muscle. Large muscles such as the quadriceps have motor units comprising many hundreds of muscle fibres, whereas in the facial muscles there may be single numbers. The movement of interdigitating filaments of myosin and actin generate muscle contraction (118). The interaction of actin with myosin is triggered by the release of calcium from the specialized endoplasmic reticulum termed the sarcoplasmic reticulum (119). This calcium release is triggered by the passage of an electrical impulse along the muscle membrane. Neuromuscular transmission is a complex process involving influx of calcium into the terminal motor axon, which then triggers the release of acetylcholine stored in presynaptic vesicles. Acetylcholine diffuses across the synaptic cleft, activates the acetylcholine receptor on the muscle membrane to allow ingress of sodium, and sets off the electrical impulse in the muscle fibre. The energy for muscle contraction is generated by glycolysis (the breakdown of glucose) occurring in the sarcoplasm and by oxidative phosphorylation taking place in the mitochondria.
Medical Countermeasures for Intoxication by Botulinum Neurotoxin
Brian J. Lukey, James A. Romano, Salem Harry in Chemical Warfare Agents, 2019
The combination of 3,4-DAP and a Ca2+ channel activator has also been used successfully to reverse the neuromuscular deficit in an experimental model of LEMS, a rare autoimmune disease in which P/Q-type Ca2+ channels at the nerve terminal are destroyed, resulting in impaired neuromuscular transmission and muscle weakness (Lundh et al., 1984; Thakkar et al., 2017). The current treatment for LEMS is 3,4-DAP, which provides significant but incomplete symptomatic relief and has dose-limiting side effects similar to those encountered in its use for treatment of botulism (Quartel et al., 2010). Tarr et al. (2014) demonstrated that GV-58, an analog of Ros with a 22-fold reduced Cdk activity and a fourfold greater Ca2+ channel agonist activity, produced supra-additive effects when used in combination with 3,4-DAP for reversing muscle weakness in a murine passive antibody transfer model of LEMS. The authors proposed that this combination will provide a better treatment not only for LEMS but also for other disorders of neuromuscular transmission.
Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody–Positive Generalized Myasthenia Gravis
Published in Expert Opinion on Investigational Drugs, 2021
James F. Howard, John Vissing, Nils E. Gilhus, M. Isabel Leite, Kimiaki Utsugisawa, Petra W. Duda, Ramin Farzaneh-Far, Hiroyuki Murai, Heinz Wiendl
Normal neuromuscular transmission is mediated by the binding of presynaptic acetylcholine to acetylcholine receptors (AChRs) in the postsynaptic membrane of the neuromuscular junction (NMJ). In MG, this transmission is impaired by autoantibodies that bind to AChRs or to functionally related molecules [1]. Anti-AChR antibodies are present in 80% to 88% of patients with MG, and contribute to early-onset (i.e., prior to 50 years of age), late-onset (i.e., ≥50 years), thymoma-associated, and ocular MG disease subtypes [5,20,21]. A smaller proportion of patients (<10%) harbor autoantibodies against muscle-specific kinase (MuSK) or lipoprotein-related protein 4 or are seronegative for all three autoantibodies [22–25]. The differences in MG antibody subtype have a major impact on treatment decisions [12]. This article focuses primarily on patients with anti-AChR antibody-positive (AChR+) gMG.
Sensory neurotization of muscle: past, present and future considerations
Published in Journal of Plastic Surgery and Hand Surgery, 2019
Steven D. Kozusko, Alexander J. Kaminsky, Louisa C. Boyd, Petros Konofaos
Williams’s research on functional return following continuous muscle stimulation after nerve injury produced promising results [36]. After completing experimental studies with animals, he published a clinical pilot study comparing continuous muscle stimulation in upper extremity nerve injuries against historical controls. An implantable system provided electrical stimulation to the denervated muscle until regeneration occurred. This functions similarly to sensory neurotization, providing support until axonal regeneration is complete. The author assessed median, ulnar, radial and combined nerve injuries for a total of 13 patients. A positive EMG confirmed nerve regeneration to the neuromuscular junction. Muscle biopsies for the subjects showed a minimal degree of atrophy at the time of electrode removal, which was completed once reinnervation was accomplished. Functional results were superior for the experimental group compared to the controls, and patients had satisfactory to excellent results based on Medical Research Council motor recovery scores. This research shows the benefit of neurotization in protecting the neuromuscular junction during reinnervation.
Marinoid J, a phenylglycoside from Avicennia marina fruit, ameliorates cognitive impairment in rat vascular dementia: a quantitative iTRAQ proteomic study
Published in Pharmaceutical Biology, 2020
Xiang-xi Yi, Jia-yi Li, Zhen-zhou Tang, Shu Jiang, Yong-hong Liu, Jia-gang Deng, Cheng-hai Gao
Signal transmission at the neuromuscular junction is mediated via the release of acetylcholine from synaptic vesicles. This process is rendered calcium-sensitive by members of the Synaptotagmin family, which also has roles in vesicle priming and in reducing spontaneous neurotransmitter release (Lee et al. 2008). SYT2 is the major isoform expressed at the neuromuscular junction, and previous studies have shown that Syt2 knockout mice show markedly reduced calcium-evoked neurotransmitter release (Pang et al. 2006). A previous study (Whittaker et al. 2015) found that Syt2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy inducing lower-limb wasting and foot deformities. A recent study (Bereczki et al. 2018) used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospective AD patients, PD patients with dementia, dementia patients with Lewy bodies, and older adults without dementia. They found a significant loss of SYT2, which implicates that it could be a synaptic marker of cognitive decline in neurodegenerative diseases. Our present study showed that abnormal expression of SYT2 may be related to the occurrence of VD, and PGs may decrease the expression of SYT2 in VD rats, thereby alleviating the symptoms of VD rats.
Related Knowledge Centers
- Action Potential
- Atrophy
- Central Nervous System
- Chemical Synapse
- Motor Neuron
- Muscle Contraction
- Peripheral Nervous System
- Muscle Tone
- Muscle Cell
- Voltage-Gated Calcium Channel